The role of antigen-specific signals in the regulation of CD4+ T cell niches in the intestine

Mucosal tissue sites such as the lung, skin, and intestine, are unique in their direct proximity to the outside world. The immune system at these sites must integrate multiple signals to balance responses appropriately. CD4+ T cells receive instructive, antigen-specific signals via T cell receptor (TCR)-major histocompatibility complex (MHCII) interactions that are important for their generation in the thymus, function, and population maintenance. Yet, the role of these signals in the regulation of CD4+ T cell populations within the mucosal intestinal niche is unclear. Studies in this thesis examined the role of MHCII in the regulatory and effector CD4+ T cell populations in the intestine. Experiments in Chapter 2 utilized a mouse model in which MHCII is restricted to the thymus; CD4+ T cells, including regulatory T cells (Tregs), develop but are not exposed to peripheral MHCII interactions. Using these mice, an ability of Tregs to preferentially fill an antigen-independent niche in the intestine was identified. This niche, once full, becomes physically isolated from the circulation independently of MHCII signals, is IL-2-independent, and is microbial signal-dependent. The conventional, non-regulatory T cell (Tconv) niche in the intestine is, compared to the Treg niche, relatively antigen-dependent. In Chapter 3, using adoptive transfer and genetic approaches, an antigen-dependent interaction of the Tconv niche with barrier-protective innate lymphoid cells (ILCs) in the intestine was revealed. Tconv down-regulate ILC homeostasis and IL-22 producing function. These data demonstrate the wide regulatory capacity of MHCII signals on CD4+ T cell niches in the intestine, and suggest that the presence or absence of these signals contribute to unique mechanisms for preserving tissue-specific tolerance and fostering host defense